tbuckley/cabot-search huggingface dataset:
Pan-cancer landscape of <i>CD274</i> (PD-L1) and <i>PDCD1LG</i>2 (PD-L2) structural variations.
Authors: Emily Louise Hoskins, Eric Samarodnitsky, Michele Wing, Julie Reeser, Julia Hopkins, Karthikeyan Murugesan, Zheng Kuang, Leah Stein, Zachary Risch, Raven Vella, Serifat Abedola, Lianbo Yu, Anoosha Paruchuri, Richard S.P. Huang, Lee A. Albacker, Sameek Roychowdhury
Journal: Journal of Clinical Oncology (2022)

3133 Background: PD-1 receptor and PD-L1 ligand interactions are the target of immunotherapies across multiple tumor types. Established biomarkers that predict response to immunotherapy are microsatellite instability, tumor mutational burden, and PD-L1 immunohistochemistry. Structural variations in CD274 (PD-L1) and PDCD1LG2 (PD-L2) have been observed in cancer, but the comprehensive landscape is unknown. Here we describe the genomic landscape of CD274 and PDCD1LG2 structural variations, their potential impact on the tumor microenvironment, and evidence that patients with these alterations can benefit from immunotherapy. Methods: We analyzed sequencing data from 514 cancer cases with CD274 and PDCD1LG2 structural variations across 25 publications and data sources, including large pan-cancer sources: Foundation Medicine, Inc (FMI), The Cancer Genome Atlas (TCGA), and Oncology Research Information Exchange Network. To evaluate immune signature enrichment, we ran the software ImSig on gene expression data. We curated literature reporting clinical outcomes of patients harboring structural variations in CD274 and PDCD1LG2. Results: From 25 studies and datasets, we curated 514 cancer cases with structural variations in PD-L1 and PD-L2, including 158 duplications, 126 deletions, 97 inversions, 178 translocations, and 96 unclassified structural variations, totaling to 655 events. We observed breakpoint ‘hotspots’ in the 3’-untranslated regions (UTRs) of PD-L1 and PD-L2. Leveraging TCGA data, we observed, in CD274-rearranged tumors, significant upregulation in PD-L1 and PD-L2 expression and signatures for interferon signaling, macrophages, monocytes, T cells, and immune cell proliferation (each p &lt; 0.001, compared to CD274 non-rearranged, copy neutral tumors). Furthermore, retrospective review of 12 studies that included patients with structural variations in CD274 or PDCD1LG2, including duplications, inversions and copy number amplifications, revealed a 73% (52/71) response rate to PD-1 immunotherapy with durable responses. Conclusions: Our evaluation of CD274 and PDCD1LG2 structural variations shows that the 3’-UTR is frequently affected and is associated with increased expression of ligands and immune signatures. Enriched interferon signaling in CD274-rearranged tumors is of particular interest, as interferon exposure is known to drive PD-L1 and PD-L2 expression. Retrospective evidence from curated studies suggests that these genomic alterations could identify candidates for PD-1 or PD-L1 immunotherapy. We expect that these findings will better define CD274 and PDCD1LG2 structural variations in cancer and support our pan-cancer prospective clinical trial to target these alterations.
Pattern of failure in inoperable stage III non-small cell lung cancer patients treated with chemoradiotherapy with/without immune checkpoint inhibition.
Authors: Julian Taugner, Lukas Käsmann, Chukwuka Eze, Alexander Nieto, Julian Guggenberger, Benedikt Flörsch, Saskia Kenndoff, Amanda Tufman, Niels Reinmuth, Claus Belka, Farkhad Manapov
Journal: Journal of Clinical Oncology (2022)

e20570 Background: We compared pattern of failure in patients treated with chemoradiotherapy (CRT) with concurrent and/or sequential Programmed Cell Death 1 (PD-1) or Ligand 1 (PD-L1) immune checkpoint inhibition (IO, immuno-oncology therapy) and CRT alone for inoperable stage III NSCLC. Methods: Prospective data of thirty nine consecutive patients who completed CRT-IO with sequential durvalumab (72%, 28 patients) or concurrent and sequential nivolumab (28%, 11 patients) and a sensitive propensity score matched (PSM adjusted for patients age, gender, T- and N-status, PTV, histology) cohort of 39 patients treated with CRT alone were analyzed. First site of failure was compared between the CRT-IO and the CRT alone subgroup. Results: All patients were treated with conventionally fractionated thoracic irradiation to a total dose of at least 60Gy (range: 60-66Gy), all patients received either sequential or simultaneous chemotherapy while 95% (74 patients; CRT-IO: 38/39; CRT alone: 36/39) received two cycles of concurrent platinum-based chemotherapy. Median follow-up for the entire cohort was 33.3 (range: 1.5-102.9) months; median overall survival (OS) was 34.9 (95%CI: 10.7-59.1) months (CRT-IO: not reached; CRT alone: 24.4, p = 0.003); median progression-free survival (PFS) was 13.6 (95% CI: 10.5-6.7) months (CRT-IO: 26.3; CRT alone: 8.3; p &lt; 0.001). At the time of evaluation 21 (53.8%) vs. 7 (17.9%) patients of the CRT-IO vs. CRT alone subgroup were progression free and alive (p = 0.003); 4 (10.3%) vs. 3 (7.7%) had brain metastases as first site of failure; 7 (17.9%) vs. 6 (15.4%) had ≤ 3 extracranial metastasis and 3 (7.7%) vs. 4 (10.3%) had multi-organ progression. Local-regional recurrence (LRR) as first site of failure was significantly less frequent in patients treated with CRT-IO vs. CRT alone, namely 3 (7.7%) vs. 12 (30.8%) patients (p = 0.001); median time to LRR was not reached vs. 15.0 (95%CI: 0.9-33.7) months. Conclusions: Pattern of failure differ significantly in patients treated with CRT-IO vs. CRT alone; CRT-IO patients are significantly less likely to develop a LRR. No differences in the prevalence of brain metastases as first site of failure could be detected.
Circulating tumor DNA is a potential prognostic risk factor of recurrence in patients with hepatocellular carcinoma treated by liver transplantation.
Authors: Nan Jiang, Xinchen Zeng, Jianxin Tang, Ziming Liang, Xiaofang Qi, Lujia Huang, Fei Pang
Journal: Journal of Clinical Oncology (2022)

e16196 Background: Liver transplantation (LT) is one of the most effective therapeutic strategies for hepatocellular carcinoma (HCC), however, tumour recurrence after LT often leads to poor outcomes. At present, clinical characteristic profile, imaging diagnosis as well as level of serum biomarkers prior to LT could predict the prognosis in HCC patients treated by LT. However, the sensitivity and specificity of these biomarkers are limited, highlighting the crucial need to identify novel biomarkers. Previous clinical studies have shown that postoperative circulating tumor DNA (ctDNA) can be used as a predictive biomarker for the risk of recurrence in stage I-III solid tumor. This study aimed at investigating the relationship between the level of ctDNA and the probability of recurrence in HCC patients treated by LT. Methods: HCC patients receiving LT treatment were enrolled. Peripheral blood samples before LT and available matched tissue samples were collected. Targeted sequencing of 328 cancer-related genes were conducted. The clinicopathologic data of the patients was retrospectively analyzed. The predictive efficiency for recurrence after LT of different clinicopathologic parameters and ctDNA were accessed. Results: A total of 45 patients were enrolled, including 42 males (93%) and 3 females (7%), with a median age of 51 (range 31-76 years). Thirty-five patients (78%) had detectable ctDNA before LT while gene alterations were identified in tumor tissue of all the patients. Larger tumor size (&gt; 5cm), cirrhosis, portal vein tumor thrombus (PVTT) and elevated AFP level (≥400ng/ml) prior to LT were associated with higher percentage of positive ctDNA (94% vs 73%, 84% vs 75%, 88% vs 79%, 88% vs 76%, respectively). Patients with micro-vessel invasion (MVI) had higher ctDNA abundance (maxVAF, P &lt; 0.05). Interestingly, after over 3 years’ follow-up, clinical factors including MVI, PVTT, BCLC stage, maximum tumor diameter and serum AFP failed to predict disease free survival (DFS) and overall survival (OS). In contrast, the recurrence rate was remarkably augmented (48.6% vs 0%) and the median DFS was significantly decreased (390 days vs not reached, p&lt; 0.05) in patients with detectable ctDNA. Conclusions: In conclusion, ctDNA could be a potential biomarker to sensitively predict the recurrence in patients with HCC treated by LT, which may help to improve the post-transplant management of these patients.
Zanidatamab (zani), a HER2-targeted bispecific antibody, in combination with chemotherapy (chemo) and tislelizumab (TIS) as first-line (1L) therapy for patients (pts) with advanced HER2-positive gastric/gastroesophageal junction adenocarcinoma (G/GEJC): Preliminary results from a phase 1b/2 study.
Authors: Keun Wook Lee, Li-Yuan Bai, Minkyu Jung, Jieer Ying, Young Hyuck Im, Do-Youn Oh, Jae Yong Cho, Sang Cheul Oh, Yee Chao, Huiyan Li, Ping Zhou, Yuanyuan Bao, Yoon-Koo Kang
Journal: Journal of Clinical Oncology (2022)

4032 Background: Zani, also known as ZW25, is a novel HER2-targeted bispecific antibody that targets two distinct extracellular domains of HER2. Zani has shown preliminary antitumor activity and tolerability in pts with HER2+ gastroesophageal adenocarcinoma as monotherapy/with chemo in Phase 1/2 studies (NCT02892123, NCT03929666). TIS, an anti-PD-1 antibody, has demonstrated antitumor activity in pts with advanced solid tumors. Combining anti-HER2 therapy with anti-PD-1 therapy and chemo increased tumor response in G/GEJC in a Phase 3 clinical trial. Methods: Cohort 2 of this ongoing open-label, Phase 1b/2 study was in pts with untreated locally advanced/metastatic HER2+ G/GEJC (NCT04276493). Cohort A received zani 30 mg/kg IV, Cohort B received zani 1800 mg IV (weight &lt; 70 kg) or 2400 mg IV (weight ≥ 70 kg), both with TIS 200 mg IV and capecitabine/oxaliplatin (CAPOX) Q3W. Primary endpoints were safety and investigator (INV)-assessed objective response rate (ORR) per RECIST v1.1. Secondary endpoints included INV-assessed duration of response (DoR), disease control rate (DCR) and progression-free survival (PFS). Results: As of Nov 26, 2021, 33 pts with a median age of 64.0 years (range: 29.0–80.0) were assigned to Cohort A (n=19) or B (n=14). Median study follow-up was 7.7 months (range: 2.1–19.0) and the median number of treatment cycles was 10 (range: 1–28), 20 (60.6%) pts remained on treatment. All pts were efficacy evaluable ([EE], n=33), confirmed ORR was 72.7% (95% CI: 54.5, 86.7). Median PFS was 10.9 months (95% CI: 6.9, NE). Efficacy data are summarized in the Table. All pts experienced ≥ 1 treatment emergent adverse event (TEAE), and 24 (72.7%) pts experienced ≥ Grade 3 TEAEs. All pts experienced treatment related TEAEs (trTEAEs), 20 (60.6%) pts experienced ≥ Grade 3 trTEAEs and trTEAEs leading to death occurred in two (6.1%) pts. Immune-mediated AEs (imAEs) occurred in nine (27.3%) pts, of which seven (21.2%) pts experienced ≥ Grade 3 imAEs. Conclusions: Zani, TIS and CAPOX combination demonstrated a manageable safety profile and antitumor activity as 1L therapy for pts with HER2+ G/GEJC. Clinical trial information: NCT04276493. [Table: see text]
Complementary role for circulating tumor DNA and tumor tissue to detect clinical relevant alterations in patients with castrate-sensitive prostate cancer.
Authors: Bin Yang, Baijun Dong, Wei Chen, Tingting Zhao, Guanjie Yang, Jun Xie, Ruiliang Wang, Hong Wang, Longfei Huang, Tongtong Liu, Menghuan Zhang, Hang Huang, Bo Peng, Wei Xue, Xudong Yao
Journal: Journal of Clinical Oncology (2022)

e17050 Background: Targeted sequencing of circulating tumor cell DNA (ctDNA) has been well studied in patients with metastatic castration-resistant prostate cancer (mCRPC), while its application in patients with castrate-sensitive prostate cancer (CSPC) is relatively limited. This study aimed to analyze the concordance of somatic alterations in ctDNA and matched tumor tissue samples oand investgate the clinical significance of genomic alterations in CSPC patients. Methods: 184 CSPC patients from three Chinese Hospitals were included (24 with localized PCa (LP), 46 with lymph node metastases (LNM), 42 with distant metastases of low tumor burden (LTB), and 72 with distant metastases of high tumor burden (HTB)). All patients had ctDNA samples and matched tumor tissues collected at time of primary biopsy (n = 78) or radical surgery (n = 106) for high-throughput targeted sequencing of multiple-gene. 36 prostate cancer clinical relevant genes were selected for analysis. Kaplan–Meier survival curves and Cox regression analyses were used to determine the associations of genomic alterations and the time to CRPC. Results: Overall, 70.6% of CSPC patients had somatic alterations in tumor tissues, which was much higher than that in ctDNA (31.5%). The concordance for alterations detected in ctDNA and matched tumor tissue was 29.2%. In subgroup analysis, the concordance for LP, LNM, LTB and HTB group were 0%, 5.3%, 3.3%, and 49.1%, respectively. Most of alterations identified were unique in tumor tissues or ctDNA. Number of alterations in tumor tissue alone was 23, 54, 58 and 56 in LP, LN, LTB and HTB group, respectively. Number of alterations alone in ctDNA was 16, 27, 9 and 37 in LP, LN, LTB and HTB group, respectively. Combined analysis of the genomic alterations identified in ctDNA and tumor tissue demonstrated that the most frequent altered gene was FOXA1 (35%), TP53 (16%), SPOP (12%), CDK12 (12%) and NCOR2 (9%). For patients with distant metastases harboring any pathogenic somatic or germline alterations of CDK12/TP53/BRCA1/BRCA2/PTEN/RB1, the median time to CRPC was significantly shorter than wide-type patients (median, 17.3 mo vs Not reached；p＜0.005). In the multivariate COX analysis, alterations of CDK12/TP53/BRCA1/BRCA2/PTEN/RB1 was still found to be significant (P = 0.00737). Conclusions: The concordance of gene alterations in ctDNA and mathced tumor tissue in CSPC patients increased with disease progression. ctDNA or tumor tissue alone was insufficient to capture all clinically relevant alterations, and therefore combined use of them may provide more comprehensive information about prognosis and clinical treatment guidance for CSPC patients. Alteration of CDK12/TP53/BRCA1/BRCA2/PTEN/RB1 was an independent prognostic factor for the time to CRPC.
Etiology of oral candidiasis in patients with oropharyngeal cancer.
Authors: Yulia V. Ulianova, Olga Yu. Kutsevalova, Irina V. Pustovaya, Viktoriya L. Volkova, Mamuka V. Bauzhadze, Natalia A. Chertova, Elena G. Goncharova, Mary L. Maldonado
Journal: Journal of Clinical Oncology (2022)

e18068 Background: The purpose of this study was to assess the etiology of oral candidiasis in patients with oropharyngeal cancer as potential causative agents of invasive candidiasis and to analyze in vitro activity of isolates of Candida fungi to caspofungin, fluconazole and voriconazole. Methods: Isolates were obtained in a prospective study from the oral mucosa of patients with oropharyngeal cancer in 2020-2021. Identification of Candida fungi was performed using MALDI-TOF MS. Result of activity of isolates to caspofungin, fluconazole and voriconazole after 24 hours of incubation were registered according to CLSI M60-ED2:2020 (Performance Standards for Antifungal Susceptibility Testing of Yeasts). Results: 45 patients aged 30-85 years were examined. 92 isolates of Candida fungi were obtained: C. albicans 31.5% (29) and Candida non albicans 68.5% (63). Candida non albicans included: C.parapsilosis 30.2% (19), C.glabrata 28.6% (18), C.krusei 19.0% (12), C.tropicalis 15.9% (10), C.guilliermondii 6.3% (4). Candida carriage on the oral mucosa was noted in 62.2% of patients in the first days of hospitalization, with a predominance of C. albicans 42.8% compared with 32.1% after chemotherapy (p = 0.003) and 25.0% after antibiotic therapy. The distribution of species varied depending on the age of patients. The table presents comparative activity of caspofungin, fluconazole and voriconazole (susceptible (S), moderately resistant (I), resistant (R)) in % to Candida spp. High sensitivity to caspofungin was noted for both C.аlbicans and Candida non albicans. Voriconazole was characterized by lower sensitivity and natural resistance in C.glabrata which makes it less suitable for empirical therapy, as well as fluconazole. Conclusions: Candida non albicans (68.5%) were predominant in the oral candidiasis etiology in patients with oropharyngeal cancer, which was probably due to the use of azole antimycotics for prevention and empirical therapy. Reduced activity to voriconazole and fluconazole was observed in the dominant isolates, given the natural resistance of C. krusei to fluconazole and C. glabrata to voriconazole. Acquired azole resistance was noted for C. parapsilosis and C. albicans. The pathogen type should be determined in all cases of invasive candidiasis to exclude natural resistance and sensitivity to azoles before starting therapy.[Table: see text]
Distribution features of genomic amplifications in microsatellite stable Chinese colorectal cancer.
Authors: Zhenhuai Yang, Guanning Li, Junjie Yang, Zetian Yang, Yi Geng, Zhenjun Shi, Xinyi Liu, Mengli Huang
Journal: Journal of Clinical Oncology (2022)

e15509 Background: Genomic amplification is key mutational events in microsatellite stable (MSS) colorectal cancer (CRC). A distinctive amplification region of CRC is Chr20q. It was revealed by several investigations the most recurrent amplified band in CRC and often co-exist with Chr8q. However, there is very little data to describe the characteristics of chromosome co-exist amplifications in CRC. We did an exploratory analysis in this issue in a large size of Chinese CRC. Methods: A total of 1977 CRC with detected genomic amplifications were included in this analysis. Calling of single nucleotide variants (SNV), copy number variants (CNV), insertion/deletions (indels), fusions were performed using a wide panel next-generation sequencing (NGS) testing. Amplifications were stratified as high-level, moderate-level and low-level according to the number of copies (cut-off: 20, 8 copies). Results: Nine chromosome arm were detected amplified in more than 10% cases in this cohort. Chr20q (65.9%), Chr13q (57.1%) and Chr8q (34.3%) were the most frequent. Chr17q and Chr12q had more high-level amplifications than other chromosome arms with ratio of 54.9% and 33.7%, respectively. In contrast, Chr20q and ChrX substantially had low-level amplifications. 36.2% (715/1977) cases had amplifications on more than two chromosome arms (median 2, range 2-7). In patients (92%) with 2-4 co-current amplified chromosome arms, the most frequent co-amplified patterns were Chr20q-Chr13q (20%) and Chr20q-Chr8q (15%). Most patients among this subgroup had more than three amplified genes in Chr20q while only one amplified gene in Chr8q. In patients (8%) with 5-7 co-current amplified chromosome arms, the most frequent amplified regions were Chr20q, Chr8q and Chr7q, and more than 60% cases harbored Chr20q-Chr8q. Interestingly, these patients mainly had multiple amplified genes in Chr8q and only one amplified gene in Chr20q, in the contrary to the patients with 2-4 co-current amplified chromosome arms. In addition, high-level focal amplifications in Chr17q and Chr12q participated equally to the amplifications with other chromosome arms. Conclusions: Our analysis results suggested the heterogeneity of Chr20q co-amplifications patterns in CRC. Amplifications in Chr20q and Chr8q may play distinct critical roles in the tumorigenesis of CRC. High-level amplifications were, on the other hand, independent of their driven process.
Comprehensive profiling of the molecular characteristics of both primary tumor and local metastases tumor in Chinese lung cancers.
Authors: Nannan Guo, Zhongying Jing
Journal: Journal of Clinical Oncology (2022)

e20517 Background: Metastasis tumor is the leading cause of lung cancer-related deaths, including local metastasis and distant metastasis. Despite its crucial clinical significance, local metastasis of lung cancer is still largely uncharacterized in terms of underlying molecular mechanisms. Here, we performed TSO500 (Illumina, San Diego, CA, USA) sequencing with 19 matched lung cancer primary and local metastatic samples to comprehensively profiling of lung cancer molecular characteristics. Methods: 19 lung cancer patients with paired primary tumor and local metastatic samples were enrolled, including 16 matched primary-lymph node samples and 3 primary-pleura samples. We compared molecular characteristics, including SNV and TMB, of matched samples. Molecular alterations identified were classified into shared (mutations in both primary and metastases) and private (mutations only in primary or metastases) groups. Thus, share mutation statistical analysis, pathway level enrichment and mutational signature was also done. Results: Comprehensively analysis of matched samples showed that mutational concordance between primary tumor and local metastases is lower. The average rate of concordance of primary-lymph node and primary-pleura was 40.6%±28.4%, 39.0%±33.9% respectively. Obviously, no difference in TMB between local metastases and primary tumor was found, average of primary vs lymph node and primary vs pleura was 7.5 vs 6.5, 6.9 vs 4.2 respectively. Significantly, we found that smoking lung cancer patients have higher TMB compared to non-smokers(p &lt; 0.01), regardless primary tumor or metastatic lymph nodes. Conclusions: Lung cancer has higher inter-tumor heterogeneity with proportion of shared mutations less than 50%. Meanwhile, smoking lung cancer has higher TMB in both primary tumor and metastatic lymph nodes compared to non-smokers.
The COVID-19 in oncological settings: The buffering role of the physician’s empathic communication protects from the impact of fear on hopelessness.
Authors: Alessandro Rossi, Maria Marconi, Federica Taccini, Stefania Mannarini, Claudio Verusio
Journal: Journal of Clinical Oncology (2022)

e24126 Background: During the lockdown related to the recent COVID-19 pandemic, many oncological patients, in addition to the fear of the COVID-19, have also experienced a sense of hopelessness related to the difficult management of their medical and oncological care. However, several studies showed that the physician’s empathic communication about medical care management may act as a buffer against this negative relationship. Thus, the study aimed to test a model in which the physician’s empathic communication mediates the relationship between fear of COVID-19 and hopelessness related to aforementioned difficulties. Methods: A sample of 70 oncological outpatients [36 females (51.4%), aged from 40 to 81 years ( mean = 65.94, SD = 11.13)] were recruited at the Department of Medical Oncology, Presidio Ospedaliero di Saronno, ASST Valle Olona. An ad hoc structured interview was developed to assess: (A) fear of COVID-19 (KR20: 0.86); (B) feelings of hopelessness related to the COVID-19 (KR20: 0.80); and (C) the patient's perception of empathy shown by the physician in communicating care management during the pandemic (KR20: 0.71). The factor score of each dimension was used as the total score. A mediation analysis (10,000 bootstrap resampling) was performed. Results: The mediation model showed statistical significance: F = 31.852, p &lt; 0.001; R 2 = 0.487. The relationship between ‘fear of COVID-19’ and ‘hopelessness’ was partially mediated by physician’s empathic communication ( path c’: β = 0.369, se = 0.096, 95%CI[0.177; 0.561], p &lt; 0.001) – revealing its buffering role; path a: β = -0.488, se = 0.073, 95%CI[-0.634; -0.342], p &lt; 0.001; path b: β = -0.375, se = 0.124, 95%CI[-0.623; -0.128], p = 0.003. Conclusions: These results highlight the protective role (buffer) of the physician’s empathic communication in the process that leads to hopelessness from the fear of COVID-19. Results suggest how physicians as well as psycho-oncologists should structure stronger interventions – based on the improvement of communication strategies – that may lead to an improvement of patients’ quality of life.